Lixivaptan (VPA-985), being developed by Biogen Idec and Cardiokine, under license from Wyeth (now part of Pfizer), is a non-
peptide, selective
vasopressin V2 receptor antagonist for the potential oral treatment of
hyponatremia associated with
heart failure.
Arginine vasopressin, the native
V2 receptor ligand, stimulates water reabsorption via activation of
V2 receptors that are expressed in the collecting ducts of the kidney. In preclinical studies,
lixivaptan displayed competitive antagonist activity at
V2 receptors in vitro, and increased urine volume and decreased urine osmolality in rats and dogs. The therapeutic benefits of
lixivaptan are being evaluated in patients with conditions that are associated with water excess and
hyponatremia. Phase II clinical trials in patients with
congestive heart failure,
liver cirrhosis with
ascites or syndrome of inappropriate
antidiuretic hormone have demonstrated that, unlike traditional
diuretics,
lixivaptan increases water clearance without affecting renal
sodium excretion or activating the neurohormonal system. Administration of
lixivaptan in combination with the
diuretic furosemide has been tested in rats as well as in trials in healthy volunteers, in which the two agents were well tolerated. Ongoing phase III trials will determine the role of
lixivaptan in the management of
hyponatremia, especially when associated with
heart failure.